Stressor exposure is a primary causal factor in the development of psychiatric disorders such as depression, anxiety, and post-traumatic stress disorder (PTSD). Stress-related psychiatric disorders are accompanied by disturbances in learning &memory. Individuals with PTSD, for example, can display distorted memory of the traumatic event, including fragmented memory, amnesia, &flashbacks. In addition, PTSD sufferers display generalization of fear &/or sensitization to mild stressors. Although it is clear that stressor exposure can alter learning &memory processes, the mechanisms underlying stress-induced amnesia, generalization, &sensitization remain elusive. Additionally, factors that can provide resilience against the development of stress-related psychiatric disorders including PTSD remain unknown. Physical activity is one behavioral manipulation that can reduce the incidence &severity of anxiety disorders, including PTSD. Voluntary exercise in rats also provides resistance against behavioral effects of stressor exposure &can improve hippocampal- dependent learning &memory processes. The interactions between exercise &stress on learning &memory have, however, yet to be investigated. Rats exposed to an acute, unpredictable stressor, display 1) amnesia of the stressor context, 2) fear generalization, &3) sensitization to novel stressors. These particular consequences of stressor exposure are dependent on the unpredictability of the stressor, persist for weeks, &resemble long- lasting symptoms of human PTSD. Hippocampal dysfunction could contribute to stress-induced learning &memory impairments by making it difficult to distinguish safe contexts from dangerous ones [1, 2]. Indeed, our preliminary data indicate that stress-induced amnesia can be caused by a disruption in consolidation of the memory of the stressor context that typically occurs in the hippocampus. Additionally, weaker context memories can lead to greater generalization of fear. Six wk of wheel running prevents stress-induced amnesia, perhaps by improving the ability to consolidate the hippocampal-dependent memory of the stressor context. Norepinephrine (NE) &brain-derived neurotrophic factor (BDNF) are 2 factors that could contribute to improved hippocampal-dependent learning &memory following exercise. Wheel running increases NE &BDNF content in the hippocampus &the exercise-induced increase in BDNF occurs via a NE &2-adrenergic receptor- dependent mechanism. Based on these data, we hypothesize that 1) stress-induced fear generalization &sensitization are dependent on disruption of hippocampal-dependent consolidation of the stressor context &2) exercise prior to stressor exposure prevents stress-induced amnesia, generalization, &sensitization through a 2-adrenergic receptor-dependent mechanism. PUBLIC HEALTH RELEVANCE: The goal of the current proposal is to investigate the protective effects of physical activity against stress-induced learning and memory impairments, focusing specifically on interactions between the 2 adrenergic receptor, brain-derived neurotrophic factor, and the hippocampus. The results of this work will improve our basic understanding of the effects of stressor exposure on learning and memory processes and the neurobiology of stress-related psychiatric disorders, and could lead to novel therapeutic strategies to prevent or reverse the detrimental consequences of stressor exposure on mental health.